Natural compounds improve diabetic nephropathy by regulating the TLR4 signaling pathway

Abstract

Diabetic nephropathy (DN), a severe complication of diabetes, is widely recognized as a primary contributor to end-stage renal disease. Recent studies indicate that the inflammation triggered by Toll-like receptor 4 (TLR4) is of paramount importance in the onset and progression of DN. TLR4 can bind to various ligands, including exogenous ligands such as proteins and polysaccharides from bacteria or viruses, as well as endogenous ligands such as biglycan, fibrinogen, and hyaluronan. In DN, the expression or release of TLR4-related ligands is significantly elevated, resulting in excessive TLR4 activation and increased production of proinflammatory cytokines through downstream signaling pathways. This process is closely associated with the progression of DN. Natural compounds are biologically active products derived from natural sources that have advantages in the treatment of certain diseases. Various types of natural compounds, including alkaloids, flavonoids, polyphenols, terpenoids, glycosides, and polysaccharides, have demonstrated their ability to improve DN by affecting the TLR4 signaling pathway. In this review, we summarize the mechanism of action of TLR4 in DN and the natural compounds that can ameliorate DN by modulating the TLR4 signaling pathway. We specifically highlight the potential of compounds such as curcumin, paclitaxel, berberine, and ursolic acid to inhibit the TLR4 signaling pathway, which provides an important direction of research for the treatment of DN.

Keywords: Diabetic nephropathy; Inflammation; Natural compounds; Toll-like receptor 4.

Graphical abstract

Fig. 1

Inflammatory pathogenesis of diabetic nephropathy (DN). The release of damage-associated molecular patterns (DAMPs) by renal cells in the diabetic setting activates various inflammation-related signaling pathways leading to DN. AGEs: advanced glycation end products; PRRS: pattern recognition receptors; NF-κB: nuclear factor kappa-B; MAPK: mitogen-activated protein kinase; TGF-β: transforming growth factor-β; GBM: glomerular basement membrane.

Fig. 2

The Toll-like receptor 4 (TLR4) signaling pathway. TLR4 induces an immune-inflammatory response through two major signaling pathways: the myeloid differentiation factor 88 (MyD88)-dependent and MyD88-independent pathways. TIRAP: Toll-interleukin 1 receptor (TIR) domain-containing adapter protein; IRAK4: interleukin (IL)-1 receptor-associated kinase 4; TRAF6: tumor necrosis factor receptor-associated factor 6; MAPK: mitogen-activated protein kinase; IKK: inhibitory kappa B kinase; IκB: inhibitory kappa B; NF-κB: nuclear factor kappa-B; AP-1: activator protein-1; TRIF: TIR domain-containing adaptor inducing interferon (IFN)-β; TRAM: TRIF-related adaptor molecule; RIP1: RIP1: receptor-interacting protein-1; TBK1: TRAF family member-associated NF-κB activator (TANK)-binding kinase 1; IRF3: IFN regulatory factor 3.

Fig. 3

The role of Toll-like receptor 4 (TLR4) in diabetic nephropathy (DN). In DN, the expression of TLR4 with related ligands is significantly upregulated in renal cells, and the expression of related inflammatory factors is increased, leading to renal injury. GBM: glomerular basement membrane; HMGB1: high mobility group box 1; MCP-1: monocyte chemotactic protein-1; TNF-α: tumor necrosis factor-α; TGF-β: transforming growth factor-β; CXCL10: C−X−C motif chemokine 10; IL-6: interleukin-6.

Fig. 4

Natural compounds that improve diabetic nephropathy (DN) by modulating the Toll-like receptor 4 (TLR4) signaling pathway. DMDD: 2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione.